This invention relates to certain novel analogs of the naturally occurring prostaglandins. In particular, it relates to novel 11-desoxy-16-aryloxy-.omega.-tetranorprostaglandins and various novel intermediates useful in their preparation.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. Each of the known, naturally occurring prostaglandins is derived from prostanoic acid which has the structure and position numbering: ##STR1## [Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein.] A systematic name for prostanoic acid is 7-[(2.beta.-octyl)-cyclopent-1.alpha.-yl]heptanoic acid.
PGA.sub.2 has the structure: ##STR2##
PGB.sub.2 has the structure: ##STR3##
PGE.sub.2 has the structure: ##STR4##
PGF.sub.2.alpha. has the structure: ##STR5##
PGF.sub.2.beta. has the structure: ##STR6##
Each of the PG.sub.1 prostaglandins, PGE.sub.1, PGF.sub.1.alpha., PGF.sub.1.beta., PGA.sub.1, and PGB.sub.2, has a structure the same as the corresponding PG.sub.2 compound except that the cis double bond between C-5 and C-6 is replaced by a single bond. For example, PGA.sub.1 has the structure: ##STR7##
The PG.sub.0 compounds are those in which there are no double bonds in either side chain. For instance, PGE.sub.0 has the structure ##STR8##
Broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.
The side-chain hydroxy at C-15 in the above formulas is in S configuration. [See, Nature, 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.]
Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e. the dextrorotatory and levorotatory forms. As drawn above, each structure represents the particular optically active form of the prostaglandin which is obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, or by carbonyl and/or double bond reduction of that prostaglandin. [Bergstrom et al., cited above.] The mirror image or optical antipode of each of the above structures represents the other enantiomer of that prostaglandin.
For instance, the optical antipode or PGF.sub.2.alpha. (ent-PGF.sub.2.alpha.) is drawn as ##STR9##
The racemic form of a prostaglandin contains equal numbers of a particular stereoisomer and its mirror image. When reference to a prostaglandin racemate is intended, the symbols "rac" or "dl" will precede in prostaglandin name. Two structures are needed to represent a racemate. For instance, the structure of dl-PGF.sub.2.alpha. is properly represented as an equimolar mixture of PGF.sub.2.alpha. and ent-PGF.sub.2.alpha.. The terms PGE.sub.1, PGE.sub.2, PGF.sub.1.alpha. and the like as used herein will mean that stereoisomer with the same absolute configuration as the corresponding prostaglandin found in mammalian tissue.
In an optical antipode, the absolute configuration at all of the above-mentioned centers of asymmetry is inverted. In an epimer, the configuration is inverted at one or more but not all of the centers. For instance, the absolute configuration of the 15-hydroxy group in 15-epi-PGF.sub.2.alpha. is the R configuration and is shown as ##STR10## It will be noted that only the configuration at the 15-position is inverted and that at the other centers of asymmetry, namely the 8-, 9-, 11- and 12-positions, the absolute configuration is the same as that in the naturally-occurring mammalian PGF.sub.2.alpha.. Racemic mixtures of epimers may also exist for instance, if 15-keto-PGF.sub.2.alpha. is reduced with zinc borohydride or a hindered alkyl borohydride, the resulting product is a racemic mixture of 15.alpha.-hydroxy and 16.beta.-hydroxy-PGF.sub.2.alpha..
PGE.sub.1, PGE.sub.2, and the corresponding PGF.sub..alpha., PGF.sub..beta., PGA, and PGB compounds, and many of their derivatives such as the esters, acylates, and pharmacologically acceptable salts, are extremely potent inducers of various biological responses. These compounds are, therefore, potentially useful for pharmacological purposes. [Bergstrom et al., cited above.] A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGF.sub..beta., PGE and PGA compounds as shown in cardiac cannulated rats or dogs; pressor activity for the PGF.sub..alpha. compounds; stimulation of smooth muscle as shown by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of the PGE and PGA compounds as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; controlling spasm and facilitating breathing in asthmatic conditions; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury; in the case of the PGE and PGB compounds, stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments; and in the case of PGF.sub.2 and PGE compounds luteolytic activity as shown in hamsters and rats.
Prostaglandins are useful to prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in avians and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.
For example, these compounds, especially those of the E series, are useful in mammals, including man, as bronchodilators [Cuthbert, Brit. Med. J., 4: 723-726, 1969]. As nasal decongestants, the compounds are used in a dose range of about 10 .mu.g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.
The PGE compounds are useful in the treatment of asthma because of their activity as bronchodilators and/or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of routes in a number of dosage forms, e.g., orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.01 to 5 mg. per kg. of body weight are used 1 to 4 times a day. These prostaglandins can also be combined advantageously with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, epherine, etc.); xanthine derivatives (theophylline and aminophyllin); and corticosteroids (ACTH and prednisolone). Regarding use of these compounds see south African Pat. No. 68/1055.
The PGE and PGA compounds are useful in mammals, including man and animals to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. [Shaw and Ramwell, In: Worchester Symposium on Prostaglandins, Wiley (New York, 1968), pp. 55-64.] For this purpose, the compounds are administered parenterally by injection or intravenous infusion in an infusion does range of about 0.1 .mu.g. to about 500 .mu.g. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range of about 0.1 to about 20 mg. per kg. of body weight per day.
The PGE compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to move or prevent the formation of thrombi in mammals, including man, rabbits, or rats. [Emmons et al., Brit. Med. J., 2: 468-472, 1967.] These compounds are, for example, useful in the treatment and prevention of mycardial infacts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically. For rapid response, especially in emergency situation, the intraveneous route of administration is preferred. Doses in the range of about 0.005 to about 20 mg. per kg. of body weight per day are used.
The PGE compounds are especially useful in additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to the new body. Under such conditions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. Such aggregation is inhibited by the presence of a prostaglandin. For this purpose, the compound is added gradually or in single or multiple portions to be circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter or circulating fluid.
PGE and PGF.sub.2 compounds are extremely potent in causing stimulation of smooth muscle, and are also highly active in potentiating other known smooth muscle stimulators. Therefore, PGE.sub.2, for example, is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, or to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puperperium. For the latter purpose, the PGE compound is administered intravenously immediately after abortion or delivery at a dose in the range of about 0.01 to about 50 .mu.g, per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given parenterally during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day.
The PGE, PGA and PGF.sub..beta. compounds are useful as hypotensive agents and vasodilators [Bergstrom et al., Acta Physiol. Scand., 64: 332-333, 1965; Life Sci., 6:449-455, 1967] in mammals, including man. To lower systemic arterial blood pressure, the compounds are administered by intravenous infusion at the rate of about 0.01 to about 50 .mu.g. per kg. of body weight per minute, or in single or multiple doses of about 25 to 500 .mu.g. per kg. of body weight total per day. [Weeks and King, Federation Proc. 23:327, 1964; Bergstrom, et al., 1965, op. cit.; Carlson, et al., Acta Med. Scand. 183:423-430, 1968; and Carlson et al., Acta Physiol. Scand. 75:161-169, 1969. ]
The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renal disfunction, especially in cases of severely impaired renal blood flow, for example, the hepatorenal syndrome and early kidney transplant rejection. In cases of excessive or inappropriate ADH (antidiuretic hormone; vasopressin) secretion, the diuretic effect of these compounds is even greater. In anephretic states, the vasopressin action of these compounds is especially useful. Illustratively, the PGA compounds are useful in alleviating and correcting cases of edema resulting from massive surface burns, in the management of shock, etc. For these purposes, the PGA compounds are preferably firt administered by intravenous injection at a dose in the range 10 to 1000 .mu.g. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 .mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.
The PGE compounds, especially PGE.sub.1, are useful in the treatment of psoriosis (Fiboh, et. al., Nature, 254, 351 (1975)). For this purpose, the compound is administered topically at a dose of 1-500 .mu.g. 1 to 4 times daily until the desired effect is obtained.
The PGE, especially PGE.sub.2, PGF.sub..alpha., and PGF.sub..beta. compounds are useful in the induction of labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term [Karim et al, J. Obstet. Gynaec. Brit. Cwlth., 77:200-210, 1970] or in the induction of therapeutic abortion [Bygdeman et al., Contraception, 4, 293 (1971)]. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 .mu.g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. Alternative routes of administration are oral, extraammiotic or intraammiotic.
The PGE, PGF.sub..alpha., and PGF.sub..beta. compounds are useful for fertility control in female mammals [Karim, Contraception, 3, 173 (1971)] including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. By the term ovulating female mammals is meant animals which are mature enough to ovulate but not so old that regular ovulation has ceased. For that purpose, PGF.sub.2.alpha., for example, is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine are alternative routes of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.
Patents have been obtained for several prostaglandins of the E and F series ad inducers of labor in mammals (Belgian Pat. No. 754,158 and West German Pat. No. 2,034,641), and on PGE.sub.1, F.sub.2 and F.sub.3 for control of the reproductive cycle (South African Pat. No. 69/6089). It has been shown that luteolysis can take place as a result of administration of PGF.sub.2.alpha. [Labhsetwar, Nature, 230, 528 (1971)] and hence prostaglandins have utility for fertility control by a process in which smooth muscle stimulation is not necessary.
The PGE and PGF.sub.2 compounds are useful as antiarrhythmic agents (Forster, et. al., Prostaglandins, 3, 895 (1973)). For this purpose the compound is infused intravenously at a dose range of 0.5-500 .mu.g/kg/minute until the desired effect is obtained.
As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, these compounds are useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.
The PGE and PGB compounds promote and accelerate the growth of epidermal cells and keratin in animals, including humans, useful domestic animals, pets, zoological specimens, and laboratory animals. For that reason, these compounds are useful in promoting healing of skin which has been damaged, for example, by burns, wounds, and abrasions, surgery, etc. These compounds are also useful in promoting adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.
To promote the growth of epidermal cells, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances, such as when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous. Especially in topical applications, these prostaglandins may be advantageously combined with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, tetracycline and oxytetracycline; with other antibacterials such as mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone; and with corticosteroids such as hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each being used in the combination at the usual concentration suitable for its use alone.
In the preparation of synthetic pharmaceutical agents, among the principal objects is the development of analogs of naturally occurring compounds which are highly selective in their physiological activity and which have an increased duration of activity. In a series of compounds like the naturally-occurring prostaglandins which has an extremely broad activity spectrum, increasing the selectivity of a single compound usually involves the enhancement of one physiological effect and the diminution of the others. By increasing the selectivity, one would, in the case of the natural prostaglandins, expect to alleviate the severe side effects, particularly the gastrointestinal one frequently observed following systemic administration of the natural prostaglandins.
In order to achieve increased selectivity and duration of action in the prostaglandin series, many researchers have concentrated on the molecular modification of the last five carbons of the methyl-terminated side chain. One modification consists of removing one to four carbon atoms from the end of the lower side chain and terminating the chain with an aryloxy or heteroaryloxy group. Compounds of this type are described, for instance, in British Pat. No. 1,350,971, the published Dutch Patent Application No. 73/06462 and Belgian Pat. No. 806,995.
The 11-desoxy analogs of the natural prostaglandins have also been described, for instance, in the published Dutch patent publication No. 16,804, Belgian Pat. No. 766,521 and the West German Offenlegungsschrift No. 2,103,005.
The 11-desoxy analogs described below have been found to be more potent, longer acting, and more selective and possess unanticipated activities when compared to the 11-desoxy analogs of the natural prostaglandins. The present state of the art of knowledge about structure-activity correlations in the prostaglandins does not, however, permit one to explain the observed enhancement of selectivity in the 11-desoxy compounds.